| 1. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 3. |
- Kassee, Caroline, et al.
(author)
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Physical health of autistic girls and women: a scoping review
- 2020
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In: Molecular Autism. - : BMC. - 2040-2392. ; 11:1
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Research review (peer-reviewed)abstract
- Background There is a growing recognition of sex and gender influences in autism. Increasingly, studies include comparisons between sexes or genders, but few have focused on clarifying the characteristics of autistic girls/womens physical health. Methods A scoping review was conducted to determine what is currently known about the physical health of autistic girls/women. We screened 1112 unique articles, with 40 studies meeting the inclusion criteria. We used a convergent iterative process to synthesize this content into broad thematic areas. Results Autistic girls/women experience more overall physical health challenges compared to non-autistic girls/women and to autistic boys/men. Emerging evidence suggests increased prevalence of epilepsy in autistic girls/women compared to non-autistic girls/women and to autistic boys/men. The literature also suggests increased endocrine and reproductive health conditions in autistic girls/women compared to non-autistic girls/women. Findings regarding gastrointestinal, metabolic, nutritional, and immune-related conditions are preliminary and inconsistent. Limitations The literature has substantial heterogeneity in how physical health conditions were assessed and reported. Further, our explicit focus on physical health may have constrained the ability to examine interactions between mental and physical health. The widely differing research aims and methodologies make it difficult to reach definitive conclusions. Nevertheless, in keeping with the goals of a scoping review, we were able to identify key themes to guide future research. Conclusions The emerging literature suggests that autistic girls/women have heightened rates of physical health challenges compared to non-autistic girls/women and to autistic boys/men. Clinicians should seek to provide holistic care that includes a focus on physical health and develop a womens health lens when providing clinical care to autistic girls/women.
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| 4. |
- Munk-Olsen, Trine, et al.
(author)
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Maternal and infant outcomes associated with lithium use in pregnancy : an international collaborative meta-analysis of six cohort studies
- 2018
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In: Lancet psychiatry. - : Elsevier. - 2215-0374 .- 2215-0366. ; 5:8, s. 644-652
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Journal article (peer-reviewed)abstract
- BACKGROUND: Concerns about teratogenicity and maternal and offspring complications restrict the use of lithium during pregnancy for the treatment of mood disorders. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity, and congenital malformations.METHODS: In this meta-analysis, primary data from pregnant women and their children from six international cohorts based in the community (Denmark, Sweden, and Ontario, Canada) and in clinics (the Netherlands, UK, and USA) were analysed. Pregnancies were eligible for analysis if the pregnancy resulted in a liveborn singleton between 1997 and 2015, if health-related information was available for both mother and infant, and if the mother had a mood disorder (bipolar disorder or major depressive disorder) or if she had been given lithium during pregnancy (at least two dispensations of lithium during pregnancy that were dispensed any time from 1 month before conception until the delivery, or a single lithium dispensation during pregnancy when there was at least one other lithium dispensation within 6 months before or after this date). Pregnancies during which the mother had been prescribed known teratogenic drugs were excluded. Pregnancies were grouped into a lithium-exposed group and a mood disorder reference group. The main outcome measures were pregnancy complications, delivery outcomes, neonatal readmission to hospital within 28 days of birth, and congenital malformations (major malformations and major cardiac malformations). Analyses were done at each site by use of a shared protocol. Adjusted odds ratios (aORs) and 95% CIs were calculated by use of logistic regression models, and site-specific prevalence rates and ORs were pooled by use of random-effects meta-analytical models.FINDINGS: 22 124 eligible pregnancies were identified across the six cohorts, of which 727 pregnancies were eligible for inclusion in the lithium-exposed group (557 [77%] from register-based cohorts and 170 [23%] from clinical cohorts). Lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. An increased risk for neonatal readmission within 28 days of birth was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27·5% [95% CI 15·8-39·1] vs 14·3% [10·4-18·2]; pooled aOR 1·62, 95% CI 1·12-2·33). Lithium exposure during the first trimester was associated with an increased risk of major malformations (pooled prevalence 7·4% [95% CI 4·0-10·7] vs 4·3% [3·7-4·8]; pooled aOR 1·71, 95% CI 1·07-2·72) but for major cardiac malformations the difference was not significant (2·1% [0·5-3·7] vs 1·6% [1·0-2·1]; pooled aOR 1·54, 95% CI 0·64-3·70).INTERPRETATION: Considering both the effect sizes and the precision of the estimates in this meta-analysis, treatment decisions for pregnant women with mood disorders must weigh the potential for increased risks of lithium during pregnancy-in particular those associated with use of lithium during the first trimester-against its effectiveness at reducing relapse.FUNDING: None.
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| 5. |
- Szatmari, Peter, et al.
(author)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Journal article (peer-reviewed)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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